Solid medicament form with active agent distributed in flat polymer fragments

ABSTRACT

In a solid medicament form for the peroral application of active agents containing a uniform distribution of active agent in a polymer material, the polymer material is in the form of flat fragments.

This application is a 371 application of PCT/EP96/00073, filed Jan. 10,1996.

The invention relates to a solid drug form for peroral administrationcomprising one or more active compounds, which are homogeneouslydistributed in a polymeric material.

BACKGROUND OF THE INVENTION

Solid active compound inclusions in polymeric materials have alreadybeen known for a relatively long time and are employed inpharmaceuticals technology for pursuing various aims. One possibility ofsystematization of such polymer inclusions from a pharmaceuticalstandpoint is classification into fast-releasing drug forms and drugforms with modified or sustained release.

Polymer inclusions in fast-releasing drug forms are, as a rule, used toaccelerate dissolution of the active compound in the fluids of thegastrointestinal tract. According to Noyes and Whitney, the rate ofdissolution of a solid active compound is proportional to the activesurface area A of the solid and the difference between the saturationconcentration C_(s) and the actual active compound concentration Caccording to the equation $\begin{matrix}{\frac{C}{t} = {k_{1} \cdot A \cdot \left( {C_{s} - C} \right) \cdot V^{- 1}}} & (I)\end{matrix}$

in which V is the volume of fluid and the constant k₁ results from thediffusion coefficient D of the active compound in the fluid and thethickness h of the stationary diffusion layer from the formula.

One obvious pharmaceutical possibility for increasing the rate ofdissolution of active compounds accordingly lies in increasing thesurface area A, for example by micronization. In the case of poorlywettable active compounds, an effective increase in the surface area,according to the above equation (I), can also be achieved by addition ofwetting agents, since non-wetted surfaces are not included in A.

At a very low solubility C_(s) of the active compound, however, suchmeasures by themselves do not always lead to the goal, since thedifference (C_(s)−C) is very small and causes only a low rate ofdissolution. In many of these cases, a significant improvement can beachieved by inclusion of the active compounds in polymers as solidsolutions.

For example, U.S. Pat. No. 4,151,273 indicates a route for inclusion ofthe sparingly soluble active compound griseofulvin in polyethyleneglycol as a solid solution, with which faster dissolution of the activecompound in the gastrointestinal tract and therefore betterbioavailability can be achieved after peroral administration than in thecase of conventional formulations. Other examples of solid solutions ofactive compounds are to be found in J. Pharm. Sci., 54, pages 1145-1148(1965).

Active compound inclusions in the form of solid dispersions inhydrophilic polymers can also have a positive effect on dissolution ofthe active compound. For example, U.S. Pat. No. 4,933,360 describes arapidly soluble solid dispersion of chlorthalidone inpolyvinylpyrrolidone which has led to significantly improved absorptionof the active compound in subjects, compared with commercially availableformulations.

Conversely, a significant delay in the release or in the dissolution ofthe active compound can be achieved by inclusion of active compounds inless readily water-soluable polymers.

These formulations can be classified into erodable and erosion-resistantmatrices. Erodable matrices are to be understood as meaning those whicheither dissolve slowly or undergo another type of breakdown of the massin the course of the release. In these cases, the active compound is asa rule released chiefly at the margins of the polymer. On the otherhand, erosion-resistant matrices are largely retained over the course ofthe release; their solubility is very low and coherence high. Activecompounds are released from them by diffusion, and for this reason suchformulations are also called diffusion matrices.

Various processes are known for the preparation of these formulations.Mention may be made, inter alia, of so-called coprecipitates,coevaporates, coextrudates and sprayed and fused inclusions (Sucker etal., Pharmazeutische Technologie [Pharmaceutical technology], ThiemeVerlag 1991, page 250 et seq.). The expert is also familiar with furtherprocessing of such inclusions by comminution to powders, mixing withfurther auxiliaries and subsequent tablet-making or introduction intohard gelatin capsules, if they do not lead directly to drug forms whichcan be administered, as in the case of some coextrudates (see, forexample, U.S. Pat. No. 4,933,360). In addition, the conventional drugforms of tablet and hard gelatin capsule have the advantage thatextremely efficient manufacturing technologies are available in respectof metering accuracy, production rate and profitability.

Disadvantages of the prior art are the considerable expenditure oncomminution of the polymer inclusions before further processing to thefinal drug form. Depending on the material, the mill used and thegrinding conditions, comminution of the bulk goods leads to particles ofdifferent size and different shape. From the point of view of modernrequirements of the purity of medicaments, mills are usually to berejected because of their abrasion of material. With the expensivecomminution processes, there is the risk of changing the physicochemicalstate, for example by stress-initiated thermodynamic stabilization oforiginally vitreous-amorphous inclusions by crystallization or, in thecase of solid suspensions, even by substantial separation of the activecompound and polymer. Such serious changes can be counteracted by thechoice of grinding conditions, it being necessary to avoid high stresseson the formulation, and the degree of comminution tending to be keptlow. As a result, pellet-like particles of spherical to irregular shapeare obtained which, nevertheless, have the disadvantage that the ratioof their spatial extent to the surface area can considerably impairrelease of the active compound. It can thus be explained why the rate ofrelease of an active compound from pellet-like particles of a polymerwhich effects sustained release, and in which it is included, decreasesconstantly, after a relatively rapid initial release of the activecompound located close to the surface of the particles, as a result ofthe continuously increasing diffusion zones in the polymer. According tothe current prior art, this effect of increasing diffusion zones can bebypassed only by extremely fine grinding of the inclusion material,which is accompanied by the disadvantages and risks mentioned.

BRIEF SUMMARY OF THE INVENTION

This invention is based on the object of employing active compoundinclusions in polymeric material in drug formulations in a form whichdoes not have the disadvantages listed for the pellets and powders knownin the prior art.

The object is achieved by providing a solid drug form which comprises ahomogeneous distribution of active compound in polymeric material in theform of flat fragments. In this manner, it is possible to keep thediffusion zones to the polymer surface particularly short and thereforerelatively constant, fine grinding being bypassed.

DETAILED DESCRIPTION OF THE INVENTION

Flat fragments in the context of this invention are pieces or sectionswith a plaice-, platelet- or leaf-like shape, such as are formed, forexample, when film-like material is broken up. They have a considerablysmaller thickness, for example 1 μm to 500 μm, compared with theirlength and breadth, thin films or foils being preferred.

One possibility of producing such flat particles comprises rolling outparticles of spherical or irregular shape, such as can be obtained fromgentle comminution processes, between two rolls rotating in oppositedirections. A prerequisite for this method is a sufficient plasticdeformability of the inclusion material; too high an elasticity wouldnot lead to permanent flattening of the particles, while brittlematerial breaks up into smaller, irregular fragments under theseconditions.

Production of flat particles from flat, film-like material isconsiderably more advantageous and preferred. Efficient coatingtechniques are available for the production of such film-like material,these also already being employed in the pharmaceuticals industry—forexample for production of transdermal therapeutic systems. Brittleinclusion material can also be produced and further processed in thismanner. Both solid solutions and solid dispersions can be preparedaccording to the invention by this method.

Alternatively, polymer films comprising homogeneously distributed activecompound can also be produced by extrusion processes. Extrusion by meansof a conveying apparatus and a temperature-controllable slot die andsubsequent stretching is widely used in industrial film production.

It is often appropriate in the formulation of inclusion productsadditionally to add auxiliaries to the polymeric material, as well asthe active compound. These include, for example, surfactants,plasticizers, crystallization retardants, antioxidants, acids, bases andthe like.

Coarse comminution of film-like materials to flat fragments can beachieved under gentle conditions with the aid of largely abrasion-freerotary and roller crushers and with cutting machines. These machines canas a rule be adjusted such that they lead to particle sizes (length) of0.2 to 2 mm, which is the preferred particle size for the inclusionproduct. The stresses on the material here are considerably lower thanin the case of fine grinding or even micronization.

The drug forms which are preferred according to the invention aretablets and hard gelatin capsules, since they are easy to administer andare largely accepted by the patient, and also because the productiontechnologies which comply with all the current requirements in respectof observing “GMP” (Good Manufacturing Practices) guidelines forproducers of pharmaceuticals, in particular dosage accuracy, as well aseconomically efficient production of large piece numbers, are available.

In this context, the polymeric material with the included activecompound and, if appropriate, auxiliaries can be mixed with furtherauxiliaries. These include, for example, physiologically acceptablefillers, binders, flow regulators, lubricants and release agents,antioxidants, dyestuffs or pigments, aromas, wetting agents,hydrophilizing agents, hydrophobizing agents, solubility-improvingagents, disintegration modulators, substances for adjusting the pH andthe like. The mixture can then be converted into tablets or introducedinto hard gelatin capsules on conventional machines.

More than one active compound can also be incorporated into a drug formaccording to the invention, if this appears to be necessary. This can beeffected in various ways. On the one hand, it is possible to includemore than one active compound in the polymeric material itself. On theother hand, several inclusions can also be combined into one drug form.Finally, it is possible to have active compounds in included form inaddition to non-included active compounds in the same drug form. Thereis thus a large number of pharmaceutical possibilities for controllingthe rate of release of the individual active compounds, both togetherand independently of one another.

The new drug form offers an additional advantage in that it enablesmucoadhesive auxiliaries to be employed therapeutically in an effectivemanner. In particular, if the active compound is included in a polymericmaterial with mucoadhesive properties or with the addition ofmucoadhesive auxiliaries and the inclusion product is incorporated intoa fast-disintegrating tablet or capsule, a large number of flatparticles having a particularly high total contact area on the mucosaand as a result considerably improved mucoadhesiveness compared withother formulations are thus released after primary disintegration of thedrug form in the gastrointestinal tract. An intensification of all thepositive effects of mucoadhesion, such as, for example, prolonging theresidence time in the upper sections of the gastrointestinal tract and,because of the short diffusion zone, an increased absorption rate ofhigher molecular weight active compounds, can be achieved here (Lenaertset al., Bioadhesive Drug Delivery Systems, CRC Press 1990).

The release of the active compounds from the inclusions in the knownpolymers is considerably promoted and can easily be controlled, i.e.optionally accelerated or delayed, by the shape thereof as flatfragments. In dimensionally stable polymeric materials which remainundecomposed, the diffusion of the active compounds can also beaccelerated and adjusted by choice of the film thickness. In polymericmaterials which, as a result of chemical structure and molecular weight,release the active compound into the body fluid by dissolving,decomposition of the polymers, erosion or swelling, the flat form of thepolymer fragments according to the invention results in greatlyincreased possibilities in pharmaceutical terms.

What is claimed is:
 1. A peroral solid drug form in the form of a tabletor capsule having a controlled release of one or more pharmacologicallyactive compounds by diffusion, comprising fragments having a thicknessof about 1 μm to about 500 μm and comprising a polymeric materialwherein the said pharmacologically active compound or compounds arehomogeneously distributed, wherein the polymeric material iserosion-resistant over the course of the release of said one or morepharmacologically active compounds.
 2. The solid drug form according toclaim 1, in the form of fragments combined to form a tablet, wherein thefragments are pressed into the form of a tablet, directly or aftermixing with one or more auxiliaries suitable for tablet making.
 3. Thesolid drug form according to claim 1, in the form of fragments within acapsule, wherein the fragments are added to a capsule directly or aftermixing with one or more pharmaceutically acceptable auxiliaries.
 4. Thesolid drug form according to claim 1, comprising more than one activecompound.
 5. The solid drug form according to claim 1, wherein the oneor more active compounds are present in the polymeric material as asolution.
 6. The solid drug form according to claim 1, wherein the oneor more active compounds are present in the polymeric material in theform of a dispersion.
 7. The solid drug form according to claim 1,wherein the polymeric material further comprises auxiliaries selectedfrom the group consisting of surfactants, plasticizers, stabilizers,crystallization retardants, antioxidants, wick substances and substancesfor adjusting the pH.
 8. The solid drug form according to claim 1,wherein the polymeric material is in the form of a thin film.
 9. Thesolid drug form according to claim 1, wherein the polymeric material hasmucoadhesive properties.
 10. The solid drug form according to claim 1,wherein when the solid drug form is placed into a release medium, thepolymeric material is erodable in the release medium with or without thepolymeric material retaining its chemical structure.
 11. The solid drugform according to claim 1, wherein when the solid drug form is placedinto a release medium, the polymeric material is swellable in therelease medium.
 12. The solid drug form according to claim 1, whereinthe fragments are produced by a method of rolling out polymeric materialparticles having spherical or irregular shape and containing thepharmacologically active compound or compounds between two rollsrotating in opposite directions, or comminuting a film consistingessentially of said polymeric material and containing the saidpharmacologically active compound or compounds.